The continuing objectives of the proposed research are to describe and understand the biochemical and physiological mechanisms which regulate the metabolism of free fatty acids (FFA) by the liver. We propose to study the interrelationships among secretion oftriglyceride and the very low density lipoprotein (VLDL), oxidation of FFA (ketogenesis and CO2 production), lipogenesis and glycerolipid synthesis, cholesterogenesis, and hepatic steatosis. The perfused rat liver and isolated hepatocytes will be used to study alternate pathways of metabolism of FFA by the liver. These studies in vitro will be correlated with VLDL triglyceride secretion rate and estimation of VLDL utilization in the intact animal. We will continue to investigate the endocrine-dependent regulation of hepatic secretion, composition, and properties of the VLDL, and related alternate pathways of metabolism of FFA. The effect of thyroidal status, adrenoglucocorticoids, gonadal steroids, glucagon, catecholamines, and cyclic nucleotides will be studied. We plan to investigate the role of calcium (Ca++) ion as a regulator of the microsomal synthesis of glycerolipids and as a possible mediator of hormal action in hepatic lipid metabolism. We plan to continue to study the substrate (FFA)-dependent regulation of hepatic secretion, composition, and properties of the VLDL. We will continue to investigate how the various properties of a specific VLDL secreted by the liver in vitro in response to a specific FFA or mixture, affect the subsequent extra-hepatic utilization of that VLDL. Utilization will be evaluated by activity of lipoprotein lipase in vitro, and by measurement of plasma half-life (T1/2) in vivo. We will studdy the interrelationships among regulation of output the VLDL and cholesterogenesis and cholesterol esterification (activation of HMG-CoA reductase and LCAT, respectively). The effects of diet, endocrinopathies and disease on plasma lipoproteins must, in part, result from altered metabolism of FFA by the liver. Understanding of these mechanisms is the purpose of this study.